5-96765327-TAAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr5-96765327-TAAAAA-T
• rs59338324
• NM_001750.7:c.2037+24_2037+28delAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000341926.7(CAST):​c.1788+3_1788+7delAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0582 in 502,106 control chromosomes in the GnomAD database, including 178 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.072 (178 hom.)
• Consequence: CAST ENST00000341926.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.47
• Publications: 1 publications found

Genes affected

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

CAST (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 178 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341926.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.2037+24_2037+28delAAAAA		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2819-2104_2819-2100delTTTTT		intron	N/A	NP_001336173.1
	ERAP1	NM_016442.5		c.2819-2104_2819-2100delTTTTT		intron	N/A	NP_057526.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2037+3_2037+7delAAAAA		splice_region intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2819-2104_2819-2100delTTTTT		intron	N/A	ENSP00000296754.3
	CAST	ENST00000341926.7	TSL:1	c.1788+3_1788+7delAAAAA		splice_region intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 13 AN: 98896 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000110

Gnomad ASJ AF: 0.000366

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00260

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0313 AC: 381 AN: 12164 AF XY: 0.0331

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.0230

Gnomad FIN exome AF: 0.00535

Gnomad NFE exome AF: 0.0518

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0724 AC: 29192 AN: 403218 Hom.: 178 AF XY: 0.0732 AC XY: 15879 AN XY: 216804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0825 AC: 747 AN: 9060

American (AMR) AF: 0.0998 AC: 1333 AN: 13352

Ashkenazi Jewish (ASJ) AF: 0.0747 AC: 806 AN: 10788

East Asian (EAS) AF: 0.0731 AC: 1640 AN: 22424

South Asian (SAS) AF: 0.0790 AC: 2397 AN: 30330

European-Finnish (FIN) AF: 0.0550 AC: 1643 AN: 29854

Middle Eastern (MID) AF: 0.0790 AC: 131 AN: 1658

European-Non Finnish (NFE) AF: 0.0715 AC: 18909 AN: 264398

Other (OTH) AF: 0.0743 AC: 1586 AN: 21354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000131 AC: 13 AN: 98888 Hom.: 0 Cov.: 0 AF XY: 0.000199 AC XY: 9 AN XY: 45258

African (AFR) AF: 0.0000394 AC: 1 AN: 25356

American (AMR) AF: 0.000110 AC: 1 AN: 9090

Ashkenazi Jewish (ASJ) AF: 0.000366 AC: 1 AN: 2730

East Asian (EAS) AF: 0.00 AC: 0 AN: 3408

South Asian (SAS) AF: 0.00 AC: 0 AN: 2876

European-Finnish (FIN) AF: 0.00260 AC: 7 AN: 2696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 164

European-Non Finnish (NFE) AF: 0.0000594 AC: 3 AN: 50520

Other (OTH) AF: 0.00 AC: 0 AN: 1312

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59338324; hg19: chr5-96101031;